Impaired mitochondrial metabolism is a critical cancer vulnerability for MYC inhibitors

William Yang; Qianyu Guo; Songhua Quan; Zachary R. Chalmers; James B Parker; Mihai Truica; Mary F. Dufficy; Megan M. Kerber; Karthik Vasan; Dikshat G. Gupta; Adam W.T. Steffeck; Hao Pan; Mohammed Siddiqui; H. Tran Pham; Gary E. Schiltz; Debabrata Chakravarti; Navdeep S. Chandel; Sarki A. Abdulkadir

doi:10.1126/sciadv.adw5228

Impaired mitochondrial metabolism is a critical cancer vulnerability for MYC inhibitors

William Yang, Qianyu Guo, Songhua Quan, Zachary R. Chalmers, James B Parker, Mihai Truica, Mary F. Dufficy, Megan M. Kerber, Karthik Vasan, Dikshat G. Gupta, Adam W.T. Steffeck, Hao Pan, Mohammed Siddiqui, H. Tran Pham, Gary E. Schiltz, Debabrata Chakravarti, Navdeep S. Chandel, Sarki A. Abdulkadir^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

MYC is a key driver in many aggressive and therapy-resistant cancers. We have developed and characterized a small-molecule MYC inhibitor named MYCi975. To uncover combination strategies for MYC inhibitors, we conducted a genome-wide CRISPR screen using MYCi975. This screen revealed a notable synthetic lethality when MYC inhibition was paired with disruption of mitochondrial complex I components, but not other complexes. Mechanistically, MYC inhibition reduced oxidative phosphorylation and glycolysis, triggering a compensatory up-regulation of complex I genes. Consequently, genetic or pharmacological targeting of complex I sensitized tumors to MYCi975 treatment, leading to increased purine catabolism and infiltration of CD8⁺ T cells and macrophages into tumors. Additionally, a wide range of tumor cells with lower complex I expression showed increased MYC dependency. These results indicate that metabolic adaptation to MYC inhibition exposes a targetable weakness at complex I and provide a rational strategy for combination therapy with emerging MYC inhibitors.

Original language	English (US)
Article number	eadw5228
Journal	Science Advances
Volume	11
Issue number	29
DOIs	https://doi.org/10.1126/sciadv.adw5228
State	Published - Jul 18 2025

Funding

We thank L. Reynolds Jr. from the Northwestern Center for Advanced Microscopy for helping with electron microscopy design, execution, and analysis. We thank C. V. Dang for providing the P493-6 B cells. We thank NUseq and Robert H. Lurie Comprehensive Cancer Center Flow Cytometry cores of Northwestern University. We thank all Abdulkadir lab members for valuable discussions. Figure 1A was created with BioRender.com This work was supported by NIH, grants P50 CA180995 (S.A.A.) and R01 CA257258 (S.A.A. and D.C.); Prostate Cancer Foundation (PCF) TACTICAL Award (S.A.A.); and Polsky Urologic Cancer Institute (S.A.A.).

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Yang, W., Guo, Q., Quan, S., Chalmers, Z. R., Parker, J. B., Truica, M., Dufficy, M. F., Kerber, M. M., Vasan, K., Gupta, D. G., Steffeck, A. W. T., Pan, H., Siddiqui, M., Pham, H. T., Schiltz, G. E., Chakravarti, D., Chandel, N. S., & Abdulkadir, S. A. (2025). Impaired mitochondrial metabolism is a critical cancer vulnerability for MYC inhibitors. Science Advances, 11(29), Article eadw5228. https://doi.org/10.1126/sciadv.adw5228

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title = "Impaired mitochondrial metabolism is a critical cancer vulnerability for MYC inhibitors",

abstract = "MYC is a key driver in many aggressive and therapy-resistant cancers. We have developed and characterized a small-molecule MYC inhibitor named MYCi975. To uncover combination strategies for MYC inhibitors, we conducted a genome-wide CRISPR screen using MYCi975. This screen revealed a notable synthetic lethality when MYC inhibition was paired with disruption of mitochondrial complex I components, but not other complexes. Mechanistically, MYC inhibition reduced oxidative phosphorylation and glycolysis, triggering a compensatory up-regulation of complex I genes. Consequently, genetic or pharmacological targeting of complex I sensitized tumors to MYCi975 treatment, leading to increased purine catabolism and infiltration of CD8+ T cells and macrophages into tumors. Additionally, a wide range of tumor cells with lower complex I expression showed increased MYC dependency. These results indicate that metabolic adaptation to MYC inhibition exposes a targetable weakness at complex I and provide a rational strategy for combination therapy with emerging MYC inhibitors.",

author = "William Yang and Qianyu Guo and Songhua Quan and Chalmers, \{Zachary R.\} and Parker, \{James B\} and Mihai Truica and Dufficy, \{Mary F.\} and Kerber, \{Megan M.\} and Karthik Vasan and Gupta, \{Dikshat G.\} and Steffeck, \{Adam W.T.\} and Hao Pan and Mohammed Siddiqui and Pham, \{H. Tran\} and Schiltz, \{Gary E.\} and Debabrata Chakravarti and Chandel, \{Navdeep S.\} and Abdulkadir, \{Sarki A.\}",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 The Authors, some rights reserved;",

year = "2025",

month = jul,

day = "18",

doi = "10.1126/sciadv.adw5228",

language = "English (US)",

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Yang, W, Guo, Q, Quan, S, Chalmers, ZR, Parker, JB, Truica, M, Dufficy, MF, Kerber, MM, Vasan, K, Gupta, DG, Steffeck, AWT, Pan, H, Siddiqui, M, Pham, HT, Schiltz, GE , Chakravarti, D , Chandel, NS & Abdulkadir, SA 2025, 'Impaired mitochondrial metabolism is a critical cancer vulnerability for MYC inhibitors', Science Advances, vol. 11, no. 29, eadw5228. https://doi.org/10.1126/sciadv.adw5228

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T1 - Impaired mitochondrial metabolism is a critical cancer vulnerability for MYC inhibitors

AU - Yang, William

AU - Guo, Qianyu

AU - Quan, Songhua

AU - Chalmers, Zachary R.

AU - Parker, James B

AU - Truica, Mihai

AU - Dufficy, Mary F.

AU - Kerber, Megan M.

AU - Vasan, Karthik

AU - Gupta, Dikshat G.

AU - Steffeck, Adam W.T.

AU - Pan, Hao

AU - Siddiqui, Mohammed

AU - Pham, H. Tran

AU - Schiltz, Gary E.

AU - Chakravarti, Debabrata

AU - Chandel, Navdeep S.

AU - Abdulkadir, Sarki A.

PY - 2025/7/18

Y1 - 2025/7/18

N2 - MYC is a key driver in many aggressive and therapy-resistant cancers. We have developed and characterized a small-molecule MYC inhibitor named MYCi975. To uncover combination strategies for MYC inhibitors, we conducted a genome-wide CRISPR screen using MYCi975. This screen revealed a notable synthetic lethality when MYC inhibition was paired with disruption of mitochondrial complex I components, but not other complexes. Mechanistically, MYC inhibition reduced oxidative phosphorylation and glycolysis, triggering a compensatory up-regulation of complex I genes. Consequently, genetic or pharmacological targeting of complex I sensitized tumors to MYCi975 treatment, leading to increased purine catabolism and infiltration of CD8+ T cells and macrophages into tumors. Additionally, a wide range of tumor cells with lower complex I expression showed increased MYC dependency. These results indicate that metabolic adaptation to MYC inhibition exposes a targetable weakness at complex I and provide a rational strategy for combination therapy with emerging MYC inhibitors.

AB - MYC is a key driver in many aggressive and therapy-resistant cancers. We have developed and characterized a small-molecule MYC inhibitor named MYCi975. To uncover combination strategies for MYC inhibitors, we conducted a genome-wide CRISPR screen using MYCi975. This screen revealed a notable synthetic lethality when MYC inhibition was paired with disruption of mitochondrial complex I components, but not other complexes. Mechanistically, MYC inhibition reduced oxidative phosphorylation and glycolysis, triggering a compensatory up-regulation of complex I genes. Consequently, genetic or pharmacological targeting of complex I sensitized tumors to MYCi975 treatment, leading to increased purine catabolism and infiltration of CD8+ T cells and macrophages into tumors. Additionally, a wide range of tumor cells with lower complex I expression showed increased MYC dependency. These results indicate that metabolic adaptation to MYC inhibition exposes a targetable weakness at complex I and provide a rational strategy for combination therapy with emerging MYC inhibitors.

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Impaired mitochondrial metabolism is a critical cancer vulnerability for MYC inhibitors

Abstract

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